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Hypoxia-inducible factor-1α-induced differentiation of myeloid leukemic cells is its transcriptional activity independent

Oncogene volume 27, pages 519–527 (2008)Cite this article

Abstract

Hypoxia or hypoxia mimetic has been shown to induce differentiation together with the accumulation of hypoxia-inducible factor-1α (HIF-1α) protein of myeloid leukemic cells and normal hematopoietic progenitors. To provide direct evidence for the role of HIF-1α in acute myeloid leukemia (AML) cell differentiation and its mechanisms, we generated myeloid leukemic U937T transformants, in which HIF-1α was tightly induced by tetracycline withdrawal. The results showed that the conditional HIF-1α induction triggered granulocytic differentiation of these transformants, while the suppression of HIF-1α expression by specific short hairpin RNAs (shRNAs) effectively inhibited hypoxia-induced differentiation of U937 cells, as evidenced by morphology, maturation-related antigens as well as expressions of myeloid differentiation signatures and hematopoietic cells-specific cytokine receptors. The specific shRNAs-inhibited expression of HIF-1β, an essential partner for transcription activity of HIF-1, failed, while the inhibition of hematopoietic differentiation-critical CCAAT/enhancer-binding protein-α (C/EBPα) significantly eliminated HIF-1α-mediated myeloid leukemic cell differentiation. Collectively, this work provided several lines of direct evidence for the role of HIF-1α protein through its nontranscriptional activity in myeloid cell differentiation, in which C/EBPα elicits a role as an effector downstream to HIF-1α. These discoveries would shed new insights for understanding mechanisms underlying leukemogenesis and designing the new therapeutic strategy for differentiation induction of AML.

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References

  • Barreda DR, Hanington PC, Belosevic M . (2004). Regulation of myeloid development and function by colony stimulating factors. Dev Comp Immunol 28: 509–554.

    Article  CAS  Google Scholar 

  • Boer J, Bonten-Surtel J, Grosveld G . (1998). Overexpression of the nucleoporin CAN/NUP214 induces growth arrest, nucleocytoplasmic transport defects, and apoptosis. Mol Cell Biol 18: 1236–1247.

    Article  CAS  Google Scholar 

  • Chen GQ, Peng ZG, Liu W, Song LP, Jiang Y, Huang Y et al. (2006). HIF-1alpha and leukemic cell differentiation. Acta Physiol Sinica 58: 5–13.

    CAS  Google Scholar 

  • Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, Cai X et al. (1997). Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL). Blood 89: 3345–3353.

    CAS  Google Scholar 

  • Friedman AD . (2002). Transcriptional regulation of granulocyte and monocyte development. Oncogene 21: 3377–3390.

    Article  CAS  Google Scholar 

  • Hong S, Choi HM, Park MJ, Kim YH, Choi YH, Kim HH et al. (2004). Activation and interaction of ATF2 with the coactivator ASC-2 are responsive for granulocytic differentiation by retinoic acid. J Biol Chem 279: 16996–17003.

    Article  CAS  Google Scholar 

  • Huang Y, Du KM, Xue ZH, Yan H, Li D, Liu W et al. (2003). Cobalt chloride and low oxygen tension trigger differentiation of acute myeloid leukemic cells: possible mediation of HIF-1alpha. Leukemia 17: 2065–2073.

    Article  CAS  Google Scholar 

  • Huang Y, Zhao Q, Zhou CX, Gu ZM, Li D, Xu HZ et al. (2006). Antileukemic roles of human phospholipid scramblase 1 gene, evidence from inducible PLSCR1-expressing leukemic cells. Oncogene 25: 6618–6627.

    Article  CAS  Google Scholar 

  • James SY, Williams MA, Kelsey SM, Newland AC, Colston KW . (1997). The role of vitamin D derivatives and retinoids in the differentiation of human leukaemia cells. Biochem Pharmacol 54: 625–634.

    Article  CAS  Google Scholar 

  • Jiang Y, Xue ZH, Shen WZ, Du KM, Yan H, Yu Y et al. (2005). Desferrioxamine induces leukemic cell differentiation potentially by HIF-1 alpha that augments transcriptional activity of CCAAT/enhancer-binding protein-alpha. Leukemia 19: 1239–1247.

    Article  CAS  Google Scholar 

  • Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE . (2004). HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J 23: 1949–1956.

    Article  CAS  Google Scholar 

  • Liu W, Guo M, Xu YB, Li D, Zhou ZN, Wu YL et al. (2006). Induction of tumor arrest and differentiation with prolonged survival by intermittent hypoxia in a mouse model of acute myeloid leukemia. Blood 107: 698–707.

    Article  CAS  Google Scholar 

  • Mueller BU, Pabst T . (2006). C/EBPalpha and the pathophysiology of acute myeloid leukemia. Curr Opin Hematol 13: 7–14.

    Article  Google Scholar 

  • Nguyen-Khac F, Della-Valle V, Lopez RG, Ravet E, Mauchauffe M, Friedman AD et al. (2006). Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation. Oncogene 25: 4840–4847.

    Article  CAS  Google Scholar 

  • Peterson LF, Zhang DE . (2004). The 8;21 translocation in leukemogenesis. Oncogene 23: 4255–4262.

    Article  CAS  Google Scholar 

  • Rosenbauer F, Koschmieder S, Steidl U, Tenen DG . (2005). Effect of transcription-factor concentrations on leukemic stem cells. Blood 106: 1519–1524.

    Article  CAS  Google Scholar 

  • Salomon-Nguyen F, Della-Valle V, Mauchauffe M, Busson-Le Coniat M, Ghysdael J, Berger R et al. (2000). The t(1;12)(q21;p13) translocation of human acute myeloblastic leukemia results in a TEL-ARNT fusion. Proc Natl Acad Sci USA 97: 6757–6762.

    Article  CAS  Google Scholar 

  • Scortegagna M, Morris MA, Oktay Y, Bennett M, Garcia JA . (2003). The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice. Blood 102: 1634–1640.

    Article  CAS  Google Scholar 

  • Scott LM, Civin CI, Rorth P, Friedman AD . (1992). A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells. Blood 80: 1725–1735.

    CAS  Google Scholar 

  • Semenza GL . (2000). HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88: 1474–1480.

    Article  CAS  Google Scholar 

  • Stegmaier K, Ross KN, Colavito SA, O'Malley S, Stockwell BR, Golub TR . (2004). Gene expression-based high-throughput screening(GE-HTS) and application to leukemia differentiation. Nat Genet 36: 257–263.

    Article  CAS  Google Scholar 

  • Suh HC, Gooya J, Renn K, Friedman AD, Johnson PF, Keller JR . (2006). C/EBPalpha determines hematopoietic cell fate in multipotential progenitor cells by inhibiting erythroid differentiation and inducing myeloid differentiation. Blood 107: 4308–4316.

    Article  CAS  Google Scholar 

  • Tenen DG, Hromas R, Licht JD, Zhang DE . (1997). Transcription factors, normal myeloid development, and leukemia. Blood 90: 489–519.

    CAS  Google Scholar 

  • Thrash-Bingham CA, Tartof KD . (1999). aHIF: a natural antisense transcript overexpressed in human renal cancer and during hypoxia. J Natl Cancer Inst 91: 143–151.

    Article  CAS  Google Scholar 

  • Zhao KW, Li X, Zhao Q, Huang Y, Li D, Peng ZG et al. (2004). Protein kinase Cdelta mediates retinoic acid and phorbol myristate acetate-induced PLSCR1 gene expression: its role in leukemic cell differentiation. Blood 104: 3731–3738.

    Article  CAS  Google Scholar 

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Acknowledgements

We appreciate Dr DG Tenen and Dr K Sogawa for generously providing U937T cells and pEF-BOS-HIF1α plasmid, respectively. We thank Dr Shen Y of Abbott Laboratories for designing shR-α. The work is submitted in partial fulfillment of the PhD requirement of Li-Ping Song at Shanghai Institutes for Biological Sciences. This work is supported in part by grants from Ministry of Science and Technology (NO2002CB512806, No. 2006CB910104), National Natural Science Foundation of China (30630034; 30500215) and grants from Science and Technology Commission of Shanghai (05JC14032). Dr GQ Chen is a Chang Jiang Scholar of Ministry of Education of People's Republic of China and is supported by Shanghai Ling-Jun Talent Program.

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Author notes

  1. L-P Song and J Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Health Science, Shanghai Institutes for Biological Sciences and Graduate School of Chinese Academy of Sciences-Shanghai Jiao-Tong University School of Medicine (SJTU-SM), Shanghai, China

    L-P Song, J Zhang, S-F Wu, Q Zhao, J-P Cao & G-Q Chen

  2. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai, China

    Y Huang, Y-L Wu, L-S Wang & G-Q Chen

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  1. L-P Song
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  2. J Zhang
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Correspondence to G-Q Chen.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Song, LP., Zhang, J., Wu, SF. et al. Hypoxia-inducible factor-1α-induced differentiation of myeloid leukemic cells is its transcriptional activity independent. Oncogene 27, 519–527 (2008). https://doi.org/10.1038/sj.onc.1210670

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